title: Calreticulin-STAT3 signaling pathway modulates mitochondrial function in a rat model of furazolidone-induced dilated cardiomyopathy.
abstract: BACKGROUND
  Calreticulin is a Ca(2+)-binding chaperone of the endoplasmic reticulum which regulates the signal transducer and activator of transcription 3 (STAT3). The effects of the calreticulin-STAT3 signaling pathway on cardiac mitochondria and on the progress of dilated cardiomyopathy (DCM) are still unclear.
  
  
  RESULTS
  The DCM model was generated in rats by the daily oral administration of furazolidone. Echocardiographic and hemodynamic studies demonstrated enlarged LV dimensions and reduced systolic and diastolic functions at thirty weeks after the first furazolidone administration. Morphometric analysis showed significant myocardial degeneration, interstitial fibrosis, and mitochondrial swelling with fractured or dissolved cristae in the model group. Compared with the control group, the mitochondrial membrane potential (MMP) level of the freshly isolated cardiac mitochondria and the enzyme activities of cytochrome c oxidase and succinate dehydrogenase in the model group were significantly decreased (P<0.05). Real-time PCR and western-blot revealed the increased expression of calreticulin associated with decreased activity of STAT3 in the model group. When cultured neonatal rat cardiomyocytes were exposed to furazolidone, a dose-dependent decrease in cell viability and MMP, and the increase of apoptosis rate were observed. The mRNA and protein expression of CRT gradually increased with the increase of furazolidone concentration, associated with a gradual decrease of the STAT3 phosphorylation level both in the whole cell and mitochondrial fraction. When calreticulin was knocked down with siRNA in cardiomyocytes, these changes of cardiomyocytes and mitochondria induced by furazolidone were significantly attenuated.
  
  
  CONCLUSIONS
  A rat model of DCM induced by furazolidone is successfully established. The calreticulin-STAT3 signaling pathway is involved in cardiac mitochondrial injury and the progress of furazolidone induced DCM.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Wei
authors.forename: Hu
authors.initials: H
authors.lastname: Shan
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Yanhe
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xue
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Rui
authors.initials: R
authors.lastname: Yan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism; D005664:Furazolidone / Q000633:toxicity; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology*; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D037282:Calreticulin; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D005664:Furazolidone; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV